Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vesels.
An estimated 16.7 million—or 29.2% of total global deaths—result from the various forms of cardiovascular disease (CVD).
Myocardial infarction (heart attack) is a serious result of coronary artery disease. Myocardial infarction (MI) is the irreversible necrosis of heart muscle secondary to prolonged ischemia. A heart attack or myocardial infarction is a medical emergency in which the supply of blood to the heart is suddenly and severely reduced or cut off, causing the muscle to die from lack of oxygen. More than 1.1 million people experience a heart attack (myocardial infarction) each year, and for many of them, the heart attack is their first symptom of coronary artery disease. A heart attack may be severe enough to cause death or it may be silent. As many as one out of every five people have only mild symptoms or none at all, and the heart attack may only be discovered by routine electrocardiography done some time later.
A heart attack (myocardial infarction) is usually caused by a blood clot that blocks an artery of the heart. The artery has often already been narrowed by fatty deposits on its walls. These deposits can tear or break open, reducing the flow of blood and releasing substances that make the platelets of the blood sticky and more likely to form clots. Sometimes a clot forms inside the heart itself, then breaks away and gets stuck in an artery that feeds the heart. A spasm in one of these arteries causes the blood flow to stop.
γ-Butyrobetaine, from which the mammalian organism synthesises carnitine, was primarily characterised as a toxic substance which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and heart stop in diastole LINNEWEH, W. Gamma-Butyrobetain, Crotonbetain und Carnitin im tierischen Stoffwechsel. Hoppe-Seylers Zeitschdft für physiologische Chemie. 1929, vol. 181, p. 42-53. At the same time, in later papers other authors ascertained that y-butyrobetaine is extremely low toxic (LD50>7000 mg/kg, s.c.) ROTZSCH, W. Iber die Toxizitat des Carnitins und einiger verwandter Stoffe. Acta biol. med. germ. 1959, vol. 3, p. 28-36.
In the literature data on nonsubstututed γ-butyrobetaine cardiovascular effects are missed, thought it was reported HOSEIN, E. A. Pharmacological actions of γ-butyrobetaine. Nature. 1959, vol. 183, p. 328-329. that γ-butyrobetaine is a substance similar to acetyl choline with a prolonged action. However, later the same authors reported that by an error the experiments involved, instead of γ-butyrobetaine, its methyl esther which in fact possesses cholinergic properties. Contrary to the former γ-butyrobetaine was characterised as a pharmacologically inert substance HOSEIN, E. A. Isolation and probable functions of betaine esters in brain metabolism. Nature. 1960, vol. 187, p. 321-322.
As structurally related compounds to 4-[ethyl(dimethyl)ammonio] butanoate are disclosed in:                GB 1238868 A 14 Jul. 1971 were disclosed betaines, such as 4-trimethylammoniobutanoate, used for polymers. Howerver no pharmacological propeties of these betaines weren't presented;        U.S. Pat. No. 5,973,026 A (XEROX CORP) 26 Oct. 1999 were disclosed 4-trimethylammoniobutanoate and 3-[diethyl(methyl)ammonio]propionate for using for ink compositions;        LLOYD ANDREW, et al. A comparison of glycine, sarcosine, N,N-dimethylglycine, glycinebetaine and N-modified betaines as liposome cryoprotectants. Journal of pharmacy and pharmacology. 1992, vol. 44, no. 6, p. 507-511 disclosed 2-[ethyl(dimethyl)ammonio]acetate used as cryoprotectants for liposomes;        DAVID B., THOMAS, et al. Synthesis, Characterization, and Aqueous Solution Behavior of Electrolyte- and pH-Responsive Carboxybetaine-Containing Cyclocopolymers. Macromolecules. 2003, vol. 36, no. 26, p. 9710-9715 disclose 4-[diallyl(methyl)ammonio]butanoate and its synthesis starting from N,N-diallyl-N-methylaminiom and ethyl 4-bromobutanoate. The free acis is obtained from the ester in a second step using Amberlite ion exchange resin. The product is used as intermediate to synthesise polymers;        Prelog V 1930, vol. 2, p. 712-722 disclosed the synthesis of 4-trimethylammoniobutanoate starting from 4-dimethylammoniobutanoate and methyliodide;        4-Trimethylammoniobutanoate and its synthesis starting from trimethylamine and ethyl 4-bromobutanoate was described JP 2009096766 A (KONAN GAKUEN) 7 May 2009. The free acid is obtained from the ester in a second step using Amberlite ion exchange resin;        WO 2008/055843 A (KALVINSH IVARS; CHERNOBROVIJS ALEKSANDRS; VARACHEVA LARISA; PUGOVICHS OSVALDS) 15 May 2008 was described 4-trimethylammoniobutanoate and synthesis, which started from the correspondin ester and using KOH-solution;        CA 2508094 A (VIVIER CANADA INC) 20 Nov. 2006 was disclosed betaines, such as 4-trimethylammoniobutanoate, for use as medicament for accelerating collagen synthesis;        U.S. Pat. No. 5,965,615 A (TAIHO PHARMACEUTICAL CO LTD; VALSTS ZINATNISKA IESTADE BEZP) 12 Oct. 1999 was disclosed 4-trimethylammoniobutanoate as a medicament for the treatment of myocardial metabolic disorder, the same compound was disclosed in US 2007191381 A (CONCERT PHARMACEUTICALS INC) 16 Aug. 2007 for treatment of myocardial infarction.        
3- (2,2,2-Trimethylhydrazinium) propionate dihydrate is known as compound with cardioprotective properties (this substance being known under its International Nonproprietary Name of Meldonium). 3- (2,2,2-Trimethylhydrazinium) propionate is disclosed in U.S. Pat. No. 4,481,218 (INST ORGANICHESKOGO SINTEZA) 6 Nov. 1984 as well in U.S. Pat. No. 4,451,485 A (INSTITU ORCH SINTEZA AKADEMII) 29 May 1984.
It is well known that 3- (2, 2,2-trimethylhydrazinium) propionate as dihydrate is widely used for controlling carnitine and gamma-butyrobetaine concentration ratio and consequently the speed of fatty acid beta-oxidation in the body DAMBROVA M., LIEPINSH E., KALVINSH I. I. Mildronate: cardioprotective action through carnitine-lowering effect. Trends in Cardiovascular Medicine,. 2002, vol. 12, no. 6, p. 275-279.
Due to these properties, Meldonium is extensively applied in medicine as an anti-ischemic, stress-protective and cardioprotective drug in treating various cardio- vascular diseases and other pathologies involving tissue ischemia KARPOV R. S., KOSHELSKAYA O. A., VRUBLEVSKY A. V., SOKOLOV A. A., TEPLYAKOV A. T., SKARDA I., DZERVE V., KLINTSARE D., VITOLS A., KALNINS U., KALVINSH I., MATVEYA L., URBANE D. Clinical Efficacy and Safety of Mildronate in Patients With Ischemic Heart Disease and Chronic Heart Failure. Kardiologiya. 2000, no. 6, p. 69-74. In the treatment of cardiovascular diseases the mechanism of action of 3-(2,2,2-trimethylhydrazinium)propionate based on limitation of carnitine biosynthesis rate and related long-chain fatty acid transport limitation through mitochondria membranes SIMKHOVICH B. Z., SHUTENKO Z. V., MEIRENA D. V., KHAGI K. B., MEZHAPUKE R. J., MOLODCHINA T. N., KALVINS I. J., LUKEVICS E.
3-(2,2,2,-Trimethylhydrazinium)propionate (THP)—a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochemical Pharmacology. 1988, vol. 37, p. 195-202., KIRIMOTO T., ASAKA N., NAKANO M., TAJIMA K., MIYAKE H., MATSUURA N. Beneficial effects of MET-88, a γ-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction. European Journal of Pharmacology. 2000, vol. 395, no. 3, p. 217-224.